Methods for producing aripiprazole suspension and freeze-dried formulation

ABSTRACT

Disclosed are a method for producing an aripiprazole suspension, wherein the aripiprazole has a mean particle size of 1 to 10 ?m, the method comprising the steps of: (a) combining bulk aripiprazole and a vehicle to form a primary suspension; (b) subjecting the primary suspension to first pulverization using e.g., a high shear pulverizing machine, a dispersion machine that applies shear force to a material to be processed, a colloid mill, an ultrasonic dispersion machine, or a high-pressure jet type emulsifying dispersion machine to form a secondary suspension; and (c) subjecting the secondary suspension to second pulverization using e.g., a high-pressure jet type emulsifying dispersion machine to form a sterile final suspension; and a method for producing a freeze-dried formulation from the aripiprazole suspension.

TECHNICAL FIELD

The present invention relates to a method for producing an aripiprazolesuspension, and also a method for producing freeze-dried formulations.

BACKGROUND ART

Aripiprazole is a drug commonly known as an atypical antipsychoticagent. Using an aripiprazole aqueous suspension as an injectableformulation has been proposed for the administration of aripiprazole. Inparticular, a suspension obtained by suspending aripiprazole with a meanparticle size of about 1 to about 10 μm in an aqueous vehicle is knownto have excellent sustained-release properties and bioavailability(Patent Document 3).

In prior art, aseptic pulverization of bulk aripiprazole was difficultat the commercial production level. For example, a ball milling method,which uses ceramic beads widely used in wet milling, has problems: beadfriction may cause contamination; additionally, ball mills capable ofin-line sterilization are generally not commercially availablecurrently.

Moreover, the ball mill pulverization method may possibly involve aproblem of short-pass in which some large particles possibly slipthrough the beads. As shown in Patent Document 4, it is preferable touse bulk aripiprazole having a desired small particle size, preferablyhaving a mean particle size of about 100 μm or less, more preferablyabout 95% of the crystals having a particle size less than 100 μm with anarrow particle size distribution. However, production of such bulkaripiprazole having a mean particle size of about 100 μm or lessrequires particular crystallization techniques like an impinging jetcrystallization method, as described in Patent Document 4.

On the other hand, particle size reduction can be carried out using ahigh-pressure homogenizer; however, when a 10% suspension ofaripiprazole having a mean particle size of more than 100 μm ispulverized with a high-pressure homogenizer, clogging occurs in theline, precluding pulverization. Therefore, it is desired to usearipiprazole preferably with a mean particle size of 100 μm or less.

However, suspending such aripiprazole with a mean particle size of about100 μm or less in a vehicle solution is accompanied by foaming.Therefore, mixing under vacuum is necessary for the preparation of ahomogeneous suspension (see Patent Document 3, Example 1 and paragraph0089).

When mixing is carried out under vacuum, outside air may be introduced,which requires measures to prevent contamination from the externalenvironment. Improvement in this aspect is desired.

Patent Document 1 discloses a method for preparing small particlescontaining a poorly water-soluble drug, comprising the steps of:

(a) mixing at high shear an admixture of a poorly water-soluble drug andone or more surface active substances in an aqueous carrier in theabsence of an organic solvent within a first temperature range at orabove the melting point of the poorly water-soluble drug to form aheated suspension containing the drug wherein the drug is molten;

(b) homogenizing the heated suspension in a first pressure range andwithin the first temperature range to form a heated homogenatecontaining the drug wherein the drug is molten;

(c) cooling the heated homogenate to a second temperature range belowthe melting temperature of the poorly water-soluble drug to form atransiently stable, cooled homogenate containing the drug;

(d) applying a particle stabilizing energetic process to the cooledhomogenate within a second temperature range below the melting point ofthe drug and in a second pressure range to form a cooled dispersion ofstabilized small particles containing the drug; and

(e) drying the cooled dispersion to form dried small particlescontaining the poorly water-soluble drug.

However, in the method of Patent Document 1, preparation of an emulsionheated at a temperature higher than the melting point of the drug isessential, and there is a problem in maintaining the crystal form.

Patent Document 2 discloses effective solubilization or dispersion meansof poorly soluble compounds by adding a combination of a predeterminedamount of an oily component (fat), an emulsifier, and cyclodextrin. Itteaches that a homomixer is used for coarse emulsification, and that ahigh-pressure homogenizer or an ultrasonic homogenizer is used for fineemulsification. However, in Patent Document 2, the compositioncontaining a poorly soluble compound that is solubilized or dispersedtakes the form of a fat emulsion, and not an aqueous suspension.

Patent Document 3 discloses a method for preparing a sterilefreeze-dried formulation comprising the steps of:

(a) preparing sterile bulk aripiprazole having a desired particle sizedistribution;

(b) preparing a sterile vehicle for the sterile bulk aripiprazole;

(c) combining the sterile aripiprazole and the sterile vehicle to form asterile primary suspension that includes a sterile mixture of solids;

(d) reducing the mean particle size of the sterile mixture of solids inthe sterile primary suspension, e.g., by an aseptic wet milling towithin the range from about 1 to about 100 μm, particularly about 1 to10 μm, to form a sterile final suspension; and

(e) freeze-drying the sterile final suspension to form the freeze-driedformulation.

It teaches that wet ball milling is preferred as the aseptic wet millingprocedure in step (d).

Non-Patent Document 1 discloses that microfluidizers have two advantagesover other methods of decreasing a mean particle size: the finalproducts have no contaminants, and production is easily scaled up.

-   Patent Document 1: Japanese Unexamined Patent Publication No.    2003-531162-   Patent Document 2: Japanese Unexamined Patent Publication No.    2005-22989-   Patent Document 3: Japanese Unexamined Patent Publication No.    2007-509148-   Patent Document 4: Japanese Unexamined Patent Publication No.    2007-509153-   Patent Document 5: Japanese Patent No. 3760264-   Patent Document 6: Japanese Patent No. 3750023-   Non-Patent Document 1: Kathleen J. Illing, et al., “Use of    Microfluidizer Processing for Preparation of Pharmaceutical    Suspensions”, Pharm. Tech., October 1996, pages 78 to 88.-   Non-Patent Document 2: “Study on Crystal Transformation of    Aripiprazole” Satoshi Aoki, et al., The Fourth Japan-Korea Symposium    on Separation Technology (Oct. 6th-8th, 1996), p. 937-940

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

Suspensions prepared by suspending aripiprazole with a mean particlesize of about 1 to about 10 μm in an aqueous vehicle are known to haveexcellent sustained-release properties. Wet ball milling of aripiprazolepreferably having a mean particle size of about 100 μm or less, morepreferably about 95% of the crystals having a particle size of 100 μm orless, is known as a process for producing such aripiprazole suspensionswith a mean particle size of 1 to 10 μm, as shown in Patent Documents 3and 4. However, production of bulk aripiprazole having a mean particlesize of about 100 μm or less required special methods, such as animpinging jet crystallization method, for producing a bulk drug. Duringthe step of suspending the bulk aripiprazole having a mean particle sizeof about 100 μm or less in a vehicle, mixing under vacuum was necessary.

For this reason, a production method has been desired that can use bulkpowder containing aripiprazole particles with a particle size of 100 μmor more in an amount of 10% or more, preferably bulk powder with a meanparticle size of more than 100 μm, particularly about 110 μm to 1000 μm,more preferably 200 μm to 400 μm, produced by batch crystallization,without the need for vacuum mixing.

Moreover, the wet ball milling method has drawbacks: bead friction maypossibly cause contamination, and ball mills capable of in-linesterilization are currently not commercially available. Therefore, amethod that rarely induces contamination and uses a production apparatuscapable of in-line sterilization has been desired.

Means for Solving the Problems

The present inventors found that even when using bulk aripiprazolecontaining 10% or more of aripiprazole particles with a particle size of100 μm or more and having a mean particle size of 20 to 1000 μm,preferably bulk aripiprazole having a mean particle size of more than100 μm, particularly preferably 110 μm to 1000 μm, most preferably 200μm to 400 μm, the above problems can be solved by performing a firstpulverization step using a high shear pulverizing machine such as a highshear homomixer, a dispersion machine that applies shear force to amaterial to be processed, a colloid mill, an ultrasonic dispersionmachine, or a high-pressure jet type emulsifying dispersion machine suchas a high-pressure homogenizer; and further performing a secondpulverization step using a high-pressure jet type emulsifying dispersionmachine such as a high-pressure homogenizer.

The present invention has been accomplished based on these findings andfurther research, and provides the following production method:

Item 1: A method for producing an aripiprazole suspension comprising thesteps of:

(a) combining bulk aripiprazole and a vehicle to form a primarysuspension;

(b) subjecting the primary suspension to first pulverization to form asecondary suspension; and

(c) subjecting the secondary suspension to second pulverization to forma final suspension.

Item 2: The method according to Item 1, wherein in the firstpulverization of step (b), the secondary suspension is formed bypulverizing the primary suspension using a high shear pulverizingmachine, a dispersion machine that applies shear force to a material tobe processed, a colloid mill, an ultrasonic dispersion machine, or ahigh-pressure jet type emulsifying dispersion machine, and in the secondpulverization of step (c), the final suspension is formed by pulverizingthe secondary suspension using a high-pressure jet type emulsifyingdispersion machine.

Item 3: The method according to Item 1 or 2, wherein in the firstpulverization of step (b), the secondary suspension is formed bypulverizing the primary suspension using a high shear pulverizingmachine or a dispersion machine that applies shear force to a materialto be processed, and in the second pulverization of step (c), the finalsuspension is formed by pulverizing the secondary suspension using ahigh-pressure homogenizer.

Item 4: The method according to Item 3, wherein in step (c), thehigh-pressure homogenizer is used at a pulverization pressure of 300 to1000 bar.

Item 5: The method according to Item 3 or 4, wherein in step (c), thehigh-pressure homogenizer is used at a pulverization pressure of 300 to600 bar.

Item 6: The method according to any of Items 3 to 5, wherein in step(c), the high-pressure homogenizer is used at an inlet temperature of 1to 70° C.

Item 7: The method according to Item 1 or 2, wherein in the firstpulverization of step (b), the secondary suspension is formed bypulverizing the primary suspension using a high-pressure homogenizer,and in the second pulverization of step (c), the final suspension isformed by pulverizing the secondary suspension using a high-pressurehomogenizer.

Item 8: The method according to Item 1, 2, or 7 wherein in the firstpulverization of step (b), the secondary suspension is formed bypulverizing the primary suspension using the high-pressure homogenizerat a pulverization pressure of 50 to 200 bar, and in the secondpulverization of step (c), the final suspension is formed by pulverizingthe secondary suspension using a high-pressure homogenizer at apulverization pressure of 200 to 1000 bar, wherein the differencebetween the pulverization pressure in step (b) and the pulverizationpressure in (c) is 100 to 900 bar.

Item 9: The method according to Item 8, wherein in step (b), thepulverization pressure of the high-pressure homogenizer is in the rangeof 50 to 200 bar, and in step (c), the pulverization is carried outplural times and the pulverization pressure is raised stepwise withinthe range of 200 to 1000 bar.

Item 10: The method according to Item 9, wherein in step (c), the finalpulverization pressure of the high-pressure homogenizer is 300 to 600bar.

Item 11: The method according to any one of Items 7 to 10, wherein insteps (b) and (c), the high-pressure homogenizer is used at an inlettemperature of 1 to 50° C.

Item 12: The method according to any one of Items 1 to 11, wherein thevehicle contains at least one suspending agent selected from the groupconsisting of carboxymethyl cellulose, carboxymethyl cellulose salts,hydroxypropyl cellulose, hydroxypropylethyl cellulose,hydroxypropylmethyl cellulose and polyvinyl pyrrolidone.

Item 13: The method according to any one of Items 1 to 12, wherein thebulk aripiprazole contains 10% or more of aripiprazole particles with aparticle size of 100 μm or more, and has a mean particle size of 20 μmto 1000 μm.

Item 14: The method according to any one of Items 1 to 13, wherein thebulk aripiprazole has a mean particle size of more than 100 μm.

Item 15: The method according to any one of Items 1 to 14, wherein thebulk aripiprazole has a mean particle size of 110 μm to 1000 μm.

Item 16: The method according to any one of Items 1 to 15, wherein thebulk aripiprazole has a mean particle size of 200 μm to 400 μm.

Item 17: The method according to any one of Items 1 to 16, wherein thearipiprazole in the aripiprazole suspension has a mean particle size of1 to 10 μm.

Item 18: The method according to any one of Items 1 to 17, wherein thearipiprazole in the aripiprazole suspension has a mean particle size of1 to 5 μm.

Item 19: The method according to any one of Items 1 to 18, wherein thearipiprazole in the aripiprazole suspension has a mean particle size of2 to 4 μm.

Item 20: The method according to any one of Items 1 to 19, wherein thearipiprazole in the aripiprazole suspension has a mean particle size of2 to 3 μm.

Item 21: The method according to any one of Items 1 to 6, comprising thesteps of:

(I) combining sterile bulk aripiprazole with a mean particle size of 200μm to 400 μm and a sterile vehicle (preferably a sterile vehiclecontaining carboxymethyl cellulose sodium salt) to form a sterileprimary suspension;

(II) subjecting the sterile primary suspension to first pulverizationusing a high shear pulverizing machine or a dispersion machine thatapplies shear force to a material to be processed to form a sterilesecondary supension; and (III) subjecting the sterile secondarysuspension to second pulverization using a high-pressure homogenizer toform a sterile final suspension;

-   -   wherein the aripiprazole in the sterile final suspension        (namely, the desired sterile aripiprazole suspension) has a mean        particle size of 1 to 10 μm (preferably 1 to 5 μm, particularly        2 to 4 μm).

Item 22: The method according to any one of Items 1 to 21, wherein thebulk aripiprazole is in the form selected from the group consisting ofmonohydrate and Anhydride Crystals B.

Item 23: The method according to any one of Items 1 to 22, furthercomprising the step of filtering the final suspension with a filterhaving a nominal filtration rating of 10 to 225 μm.

Item 24: A method for producing a freeze-dried formulation ofAripiprazole Hydrate A, the method comprising the steps of: cooling thesuspension produced by the method according to any one of Items 1 to 23and containing Aripiprazole Hydrate A to −20 to −55° C. to freeze thesuspension; and subsequently performing drying at a temperature lowerthan about 0° C.

Item 25: A method for producing a freeze-dried formulation containingaripiprazole in anhydrous form, the method comprising the followingthree steps of:

(1) cooling the aripiprazole suspension produced by the method accordingto any one of Items 1 to 23 using bulk aripiprazole in the form of amonohydrate or anhydrous crystals to −20 to −55° C. to freeze thesuspension;

(2) performing primary drying at a temperature lower than about 0° C.;and

(3) performing secondary, drying at a temperature higher than about 0°C.

Effects of the Invention

The present invention provides excellent effects as described below.

(a) The method for producing an aripiprazole suspension according to thepresent invention, which comprises two-step pulverization of bulkaripiprazole, is particularly effective when using bulk aripiprazolecontaining at least 10% of aripiprazole particles having a particle sizeof 100 μm or more and having a mean particle size of 20 μm to 1000 μm,preferably bulk aripiprazole having a mean particle size of more than100 μm, particularly 110 μm to 1000 μm, most preferably 200 μm to 400μm. However, regardless of the mean particle size, the method of thepresent invention readily produces an aripiprazole suspension having amean particle size of 1 to 10 μm, preferably 1 to 5 μm, more preferably2 to 4 μm, and most preferably 2 to 3 μm.

(b) By carrying out two-step pulverization, in accordance with thepresent invention, i.e., a first pulverization step using a high shearpulverizing machine (e.g., a high shear homomixer), a dispersion machinethat applies shear force to a material to be processed, a colloid mill,an ultrasonic dispersion machine, or a high-pressure jet type dispersionmachine (e.g., a high-pressure homogenizer), and a second pulverizationstep using a high-pressure jet type dispersion machine (e.g., ahigh-pressure homogenizer), an aripiprazole suspension having a meanparticle size of 1 to 10 μm can be prepared, even using bulk powder witha large mean particle size, particularly bulk aripiprazole with a meanparticle size of more than 100 μm obtained by batch crystallization,etc. Therefore, unlike Patent Document 4, special crystallizationtechniques like an impinging jet crystallization method are unnecessaryfor the preparation of bulk aripiprazole.

(c) The method of the invention uses, as sterile bulk aripiprazole, thebulk aripiprazole containing at least 10% of aripiprazole particleshaving a particle size of 100 μm or more and having a mean particle sizeof 20 μm to 1000 μm, preferably bulk aripiprazole having a mean particlesize of more than 100 μm, particularly 110 μm to 1000 μm, and mostpreferably 200 μm to 400 μm, and therefore the step of combining bulkaripiprazole and a vehicle, the first pulverization step and the secondpulverization step can be performed without adopting a vacuum mixingprocess as used in Patent Document 3. This eliminates the possibility ofoutside air mixing with the formulation during production of the sterileformulation, providing great advantages for a method for producingsterile products.

(d) Moreover, since no wear occurs as in a ball mill, there are nocontamination problems caused by such wear.

(e) Short pass of large particles, which is a problem in wet ballmilling, is less likely to occur, and therefore a homogeneous suspensionfree of coarse aripiprazole particles is obtained. As a result, theAripiprazole suspension can be filtered with a smaller pore size forremoving foreign substances after pulverization, and is advantageousfrom the standpoint of foreign substance control.

(f) In commercial scale aseptic production, clean-in-place (CIP) andsterilization-in-place (SIP) are difficult with respect to apparatusessuch as ball mills; however, the production apparatus used in thepulverization method (first pulverization step and second pulverizationstep) of the invention allows for CIP and SIP. Hence, the apparatus iseasily kept sterile by in-line sterilization.

(g) When carboxymethyl cellulose or a salt thereof is selected as asuspending agent for a vehicle in the present production method, it ispossible to avoid excessive pulverization in which the mean particlesize falls below 1 μm.

BEST MODE FOR CARRYING OUT THE INVENTION

The production method of the present invention is described in detailbelow.

In the present invention, the term “mean particle size” refers to volumemean diameter as measured by laser-light scattering (LLS) methods.Particle size distribution is measured by LLS methods, and mean particlesize is calculated from the particle size distribution.

Bulk Aripiprazole

Aripiprazole has the Structure

and is an atypical antipsychotic agent useful in treating schizophrenia.It has poor aqueous solubility (<1 μg/ml at room temperature).

Aripiprazole bulk drug or bulk powder may have any mean particle sizeand particle size distribution. Generally, it is preferable to use bulkaripiprazole containing aripiprazole particles having a particle size of100 μm or more in a proportion of at least 10% and having a meanparticle size of 20 μm to 1000 μm, preferably bulk aripiprazole having amean particle size of more than 100 μm, particularly 110 μm to 1000 μm,and most preferably 200 μm to 400 μm.

Moreover, the crystal form of bulk aripiprazole is not limited andvarious forms are usable. Examples of the crystal forms of aripiprazoleinclude monohydrate disclosed in Non-Patent Document 2 (in the presentspecification, the term “a monohydrate” as such means the monohydratedisclosed in Non-Patent Document 2), Hydrate A and Anhydride Crystals Bthat are disclosed in Patent Document 5, Anhydride Crystals C, AnhydrideCrystals D, Anhydride Crystals E, Anhydride Crystals F, and

Anhydride Crystals G that are disclosed in Patent Document 6. Amongthese, a monohydrate and Anhydride Crystals B are preferable.

In the present invention, by using a monohydrate crystal (Non-PatentDocument 2) as bulk aripiprazole, a suspension of Hydrate A (PatentDocument 5) is obtained by the method of the invention. Also, by usingHydrate A as bulk aripiprazole, a suspension of Hydrate A can beobtained by the method of the invention. Anhydride Crystals B (PatentDocument 5), Anhydride Crystals C, Anhydride Crystals D, AnhydrideCrystals E, Anhydride Crystals F, and Anhydride Crystals G (PatentDocument 6) can also be used as bulk aripiprazole. With these crystals,an aripiprazole suspension in which Hydrate A and anhydrous aripiprazoleare mixed is obtained. Additionally, Anhydride Crystals B, AnhydrideCrystals C, Anhydride Crystals D, Anhydride Crystals E, AnhydrideCrystals F, or Anhydride Crystals G may be recrystallized from ethanoland water, or the like in advance to thereby prepare a monohydrate, andthe resulting monohydrate may be used as bulk Aripiprazole.

Vehicle

The vehicle used in the invention generally includes:

(1) one or more suspending agents,

(2) water for injection,

(3) optionally one or more bulking agents or isotonic agents,

(4) optionally one or more buffers, and

(5) optionally one or more pH adjusting agents.

The suspending agent will be present in an amount within the range fromabout 0.2 to about 10% by weight, preferably about 0.3 to about 5% byweight, more preferably about 0.4 to about 0.9% by weight, based on thetotal weight of the sterile injectable formulation (the aripiprazolesuspension of the invention). Examples of suspending agents suitable foruse include, but are not limited to, one, two or more of the following:carboxymethyl cellulose or a salt thereof (e.g., sodium carboxymethylcellulose), hydroxypropyl cellulose, hydroxypropylethyl cellulose,hydroxypropylmethyl cellulose, and polyvinylpyrrolidone, withcarboxymethyl cellulose or a salt thereof, particularly sodium salt,being preferred. Other suspending agents suitable for use in the vehiclefor the aripiprazole include various polymers, low molecular weightoligomers, natural products, and surfactants, including nonionic andionic surfactants, such as cetyl pyridinium chloride, gelatin, casein,lecithin (phosphatides), dextran, glycerol, gum acacia, cholesterol,tragacanth, stearic acid, benzalkonium chloride, calcium stearate,glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifyingwax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogolethers such as cetomacrogol 1000), polyoxyethylene castor oilderivatives, polyoxyethylene sorbitan fatty acid esters (e.g., thecommercially available Tweens (registered trademark); e.g., Tween 20(registered trademark) and Tween 80 (registered trademark) (ICISpecialty Chemicals)); polyethylene glycols (e.g., Carbowaxs 3350(registered trademark) and 1450 (registered trademark), and Carbopol 934(registered trademark) (Union Carbide)), dodecyl trimethyl ammoniumbromide, polyoxyethylene stearates, colloidal silicon dioxide,phosphates, sodium dodecyl sulfate, carboxymethylcellulose calcium,hydroxypropyl celluloses (e.g., HPC, HPC-SL, and HPC-L),methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose,hydroxypropylmethyl-cellulose phthalate, non-crystalline cellulose,magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA),4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide andformaldehyde (also known as tyloxapol, superione, and triton),poloxamers (e.g., Pluronics F68 (registered trademark) and F108(registered trademark), which are block copolymers of ethylene oxide andpropylene oxide); poloxamines (e.g., Tetronic 908 (registeredtrademark), also known as Poloxamine 908 (registered trademark), whichis a tetrafunctional block copolymer derived from sequential addition ofpropylene oxide and ethylene oxide to ethylenediamine (BASF WyandotteCorporation, Parsippany, N.J.)); a charged phospholipid such asdimyristoyl phosphatidyl glycerol, dioctylsulfosuccinate (DOSS);Tetronic 1508 (registered trademark) (T-1508) (BASF WyandotteCorporation), dialkylesters of sodium sulfosuccinic acid (e.g., AerosolOT (registered trademark), which is a dioctyl ester of sodiumsulfosuccinic acid (American Cyanamid)); Duponol P (registeredtrademark), which is a sodium lauryl sulfate (DuPont); Tritons X-200(registered trademark), which is an alkyl aryl polyether sulfonate (Rohmand Haas); Crodestas F-110 (registered trademark), which is a mixture ofsucrose stearate and sucrose distearate (Croda Inc.);p-isononylphenoxypoly-(glycidol), also known as Olin-10G (registeredtrademark) or Surfactant 10-G (registered trademark) (Olin Chemicals,Stamford, Conn.); Crodestas SL-40 (Croda, Inc.); and SA9OHCO, which isC₁₈H₃₇CH₂ (CON(CH₃)) —CH₂ (CHOH)₄ (CH₂OH)₂ (Eastman Kodak Co.);decanoyl-N-methylglucamide; n-decyl β-D-glucopyranoside; n-decylβ-D-maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecylβ-D-maltoside; heptanoyl-N-methylglucamide;n-heptyl-β-D-glucopyranoside; n-heptyl β-D-thioglucoside; n-hexylβ-D-glucopyranoside; nonanoyl-N-methylglucamide; n-nonylβ-D-glucopyranoside; octanoyl-N-methylglucamide;n-octyl-β-D-glucopyranoside; octyl β-D-thioglucopyranoside; and thelike.

Most of these suspending agents are known pharmaceutical excipients, andare described in detail in the Handbook of Pharmaceutical Excipients,published jointly by the American Pharmaceutical Association and ThePharmaceutical Society of Great Britain (The Pharmaceutical Press,1986), specifically incorporated by reference. The suspending agents arecommercially available and/or can be prepared by techniques known in theart.

In the invention, it is preferable to use carboxymethyl cellulose or asalt thereof, hydroxypropyl cellulose, hydroxypropylethyl cellulose,hydroxypropylmethyl cellulose, or polyvinylpyrrolidone as a suspendingagent for a vehicle. The use of carboxymethyl cellulose (hereinafteroccasionally referred to as “CMC”) or a salt thereof (preferably sodiumsalt (hereinafter occasionally referred to as “CMCNa”)) particularlyensures the prevention of excessive pulverization in which the meanparticle size falls below 1 μm, even when pulverization in the secondpulverization step is repeatedly performed or performed over a prolongedperiod.

The viscosity range of carboxymethyl cellulose or the sodium saltthereof may be suitably selected from a wide range. Generally, theviscosity of a 4% aqueous solution at 25° C. is preferably about 20 to400 cps, particularly about 50 to 200 cps.

If desired, the vehicle of the present invention may contain bulkingagent (also referred to as a cryogenic/lyophilize protecting agent) orisotonic agent. The agent will be present in an amount within the rangefrom about 1 to about 10% by weight, preferably from about 1.5 to about8% by weight, more preferably from about 2 to about 5% by weight, basedon the total weight of the sterile injectable formulation (thearipiprazole suspension of the invention). Examples of bulking agents orisotonic agents suitable for use herein include, but are not limited to,one, two or more of the following: mannitol, sucrose, maltose, xylitol,glucose, starches, sorbitol, and the like, with mannitol being preferredfor formulations where the mean particle size is about 1 micron orabove.

As required, the vehicle of the present invention may contain buffer.The buffer will be employed in an amount to adjust the pH of an aqueoussuspension of aripiprazole to from about 6 to about 8, preferably about7. To achieve such a pH, the buffer, depending on the type, will usuallybe employed in an amount within the range from about 0.02 to about 2% byweight, preferably from about 0.03 to about 0.1% by weight, based on thetotal weight of the sterile injectable formulation (the aripiprazolesuspension of the invention). Examples of buffers suitable for useherein include, but are not limited to, one, two or more of thefollowing: sodium phosphate, potassium phosphate, or TRIS buffer, withsodium phosphate being preferred.

The vehicle of the invention may optionally include a pH adjusting agentthat is employed in an amount to adjust the pH of the aqueous suspensionof aripiprazole within the range from about 6 to about 7.5, preferablyabout 7, and may be an acid or base depending upon whether the pH of theaqueous suspension of the freeze-dried aripiprazole needs to be raisedor lowered to reach the desired neutral pH of about 7. Thus, when the pHneeds to be lowered, an acidic pH adjusting agent such as hydrochloricacid or acetic acid, preferably hydrochloric acid, may be employed. Whenthe pH needs to be raised, a basic pH adjusting agent such as sodiumhydroxide, potassium hydroxide, magnesium oxide or magnesium hydroxide,preferably sodium hydroxide, will be employed.

Production Method of the Invention

The production method of the invention is described below.

As described above, the present invention provides a method forproducing an aripiprazole suspension, the method comprising the stepsof:

(a) combining bulk aripiprazole and a vehicle to form a primarysuspension;

(b) subjecting the primary suspension to first pulverization to form asecondary suspension; and

(c) subjecting the secondary suspension to second pulverization to forma final suspension.

According to one preferred embodiment of the invention, there isprovided the following method: A method for producing a sterilearipiprazole suspension in which aripiprazole has a mean particle sizeof 1 to 10 μm, preferably 1 to 5 μm, more preferably 2 to 4 μm, mostpreferably about 2 to 3 μm, the method comprising the steps of:

(A) combining sterile bulk aripiprazole and a sterile vehicle to form asterile primary suspension;

(B) subjecting the sterile primary suspension to first pulverizationusing a high shear pulverizing machine, a dispersion machine thatapplies shear force to a material to be processed, a colloid mill, anultrasonic dispersion machine, or a high-pressure jet type emulsifyingdispersion machine, to form a sterile secondary suspension; and

(C) subjecting the sterile secondary suspension to second pulverizationusing a high-pressure jet type emulsifying dispersion machine to form asterile final suspension.

In carrying out the method for preparing the sterile aripiprazolesuspension of the invention, it is required that everything be sterileso that sterile aripiprazole and a sterile vehicle are combinedaseptically to form a sterile suspension.

However, when it is possible to perform sterilization after the desiredaripiprazole suspension is obtained, the sterile aripiprazole and thesterile vehicle need not necessarily be used in the method includingsteps (A), (B) and (C) above.

(A) Step of Combining Sterile Bulk Aripiprazole and Sterile Vehicle toForm a Sterile Primary Suspension

This step (A) comprises the following steps (A-1), (A-2) and (A-3).

(A-1) Step of Preparing Sterile Bulk Aripiprazole

This step typically prepares sterile bulk aripiprazole containing 10% ormore of aripiprazole particles having a particle size of 100 μm or moreand having a mean particle size of 20 μm to 1000 μm, preferably sterilebulk aripiprazole having a mean particle size of more than 100 μm,particularly preferably 110 μm to 1000 μm, most preferably 200 μm to 400μm. The method for sterilizing bulk aripiprazole is not limited, and canbe selected from a number of methods including aseptic crystallization,autoclave sterilization, gas sterilization, and radiation sterilization.Among them, aseptic crystallization is preferred.

Aseptic crystallization is a process in which a solution prepared bydissolving aripiprazole in a solvent is sterilized by filtrationsterilization etc., and then crystallization is carried out. A number ofsuch processes, such as a continuous crystallization method or a batchcrystallization method, can be used without limitation.

Autoclave sterilization, gas sterilization, or radiation sterilizationmay be conducted in accordance with conventional methods that cansterilize aripiprazole.

The crystalline form of sterile aripiprazole is known to exist in theform of monohydrate, Hydrate A, Anhydride Crystals B, Anhydride CrystalsC, Anhydride Crystals D, Anhydride Crystals E, Anhydride Crystals F, andAnhydride Crystals G, etc., all of which may be employed in theformulation of the present invention. Among these, monohydrate andAnhydride Crystals B are most preferable.

(A-2) Step of Preparing a Sterile Vehicle for the Sterile BulkAripiprazole

A vehicle for the sterile bulk aripiprazole is prepared by uniformlydissolving the above-mentioned suspending agent, and optionally abulking agent or an isotonic agent, a buffer, and a pH adjusting agentin water for injection, and sterilizing the resulting vehicle solution.

The method for sterilizing the vehicle solution is not limited, but ispreferably filtration with a filter. The pore size of the filter ispreferably about 0.2 μm.

(A-3) Step of Combining the Sterile Aripiprazole and the Sterile Vehicleto Form a Sterile Primary Suspension

The sterile bulk aripiprazole and the sterile vehicle are asepticallymixed to form a sterile primary suspension. The aseptic mixing processis not limited as long as it is a known aseptic stirring technique, suchas an aseptic mixing method using a mechanical stirring device with apropeller. Conditions at the time of mixing are not limited. Forexample, preferable stirring conditions are such that powder particlesare mixed in a vehicle without foaming.

The concentration of the sterile bulk aripiprazole to be dispersed inthe sterile vehicle may be suitably selected from a wide range, butgenerally is about 10 to 400 mg/ml, preferably 50 to 250 mg/ml, mostpreferably about 100 mg/ml.

The mixing procedure in step (A-3) may be performed under ordinarypressure (atmospheric pressure) or increased pressure. Unlike in PatentDocument 3, there is no need to adopt vacuum or reduced pressureconditions. Under increased pressure, generally, the mixing procedure ispreferably carried out at a gauge pressure of about 0 to 0.3 MPa.Preferred temperature conditions in step (A-3) is about 5 to 80° C.,particularly about 10 to 40° C. Unlike in Patent Document 1, there is noneed to employ temperatures at or above the melting point of bulkaripiprazole.

(B) Step of Subjecting the Sterile Primary Suspension to FirstPulverization Using a High Shear Pulverizing Machine (e.g., High ShearHomomixer), a Dispersion Machine that Applies Shear Force to a Materialto be Processed, a Colloid Mill, an Ultrasonic Dispersion Machine, or aHigh-Pressure Jet Type Emulsifying Dispersion Machine (e.g.,High-Pressure Homogenizer) to Form a Sterile Secondary Suspension

The particle size of the aripiprazole is reduced to a desired level by afirst pulverization step. Examples of pulverizing machines used in thefirst pulverization step include those which can suitably produceparticles having a target particle size, such as a high shearpulverizing machine, a dispersion machine that applies shear force to amaterial to be processed, a colloid mill, an ultrasonic dispersionmachine (pulverizing machine), or a high-pressure jet type emulsifyingdispersion machine (e.g., high-pressure homogenizer). A high shearpulverizing machine or a dispersion machine that applies shear force toa material to be processed, are preferably used. As such high shearpulverizing machines, e.g., a high shear homomixer, various commercialproducts are available, such as “Clearmix” (trade name, produced byM-Technique Co., Ltd.). However, they are not limited as long as theyare high shear pulverizing machines that are air-tight and free offoaming.

Conditions under which pulverization is carried out using a high shearhomomixer may be such that a target particle size can be suitablyobtained. The target particle size may be such that the flow path of ahomogenizer used in the subsequent second pulverization step is notclogged. Typical conditions may be such that the mean particle size isreduced to about 5 to 100 μm, preferably 5 to 50 μm.

In the first pulverization step, pulverization is preferably carried outusing the above-mentioned apparatus at a rotating blade (rotor)circumferential speed of typically 5 to 50 m/s, preferably 10 to 40 m/s,and more preferably about 15 to 35 m/s. It is particularly effective tooperate a high shear pulverizing machine, such as a high shear homomixer(e.g., those available under the trade name of Clearmix), at such acircumferential speed. For example, secondary suspensions with a meanparticle size of 10 to 20 μm were obtained from a primary suspension (4L, laboratory scale) subjected to a first pulverization using a ClearmixCLM-1.5S at a circumferential speed of 28.3 m/s, as well as from primarysuspensions (40 L, scale-up) subjected to a first pulverization using aClearmix CLM-9S or Clearmix CLM-15S at a circumferential speed of 28.3m/s.

Temperature conditions in step (B) are about 5 to 80° C., particularlyabout 10 to 40° C.

In place of the high shear homomixer, a dispersion machine that appliesshear force to a material to be dispersed, namely, a dispersionapparatus that exerts shear force to aripiprazole particles duringprocessing, can be used. Various commercial products are available assuch dispersion machines, including a dispersion machine that appliesshear force to a material to be processed (trade name: “T-50 Basic”produced by IKA Japan, Inc.). Conditions for pulverization by thesedispersion machines may be such that a target particle size can besuitably obtained. The target particle size may be such that the flowpath of a homogenizer used in the subsequent second pulverization stepis not clogged. Typical conditions may be such that the mean particlesize is reduced to about 5 to 100 μm, preferably 5 to 50 μm.

Colloid mills, ultrasonic dispersion machine (pulverizing machine) orhigh-pressure jet type emulsifying dispersion machines may also be usedunder substantially the same conditions as mentioned above.

The pulverization in step (B) may be conducted under ordinary pressure(atmospheric pressure) or increased pressure. Unlike in Patent Document3, there is no need to adopt vacuum or reduced pressure conditions.Under increased pressure, generally, the mixing procedure is preferablycarried out at a gauge pressure of about 0 to 0.3 MPa.

(C) Step of Subjecting the Sterile Secondary Suspension to SecondPulverization Using a High-Pressure Jet Type Emulsifying DispersionMachine (e.g., High-Pressure Homogenizer) to Form a Sterile FinalSuspension

The particle size of the aripiprazole is reduced to a desired level by asecond pulverization step. Examples of pulverizing machines used in thesecond pulverization step include a high-pressure jet type emulsifyingdispersion machine that treats process liquids under high pressure. Apreferred high-pressure jet type emulsifying dispersion machine is ahigh-pressure homogenizer in which pump-pressurized process liquid isejected as a jet-stream at high pressure by adjusting a speciallydesigned valve in an ejecting section. Typical models of this typeinclude EmulsiFlex (produced by Avestin) and high-pressure homogenizersproduced by APV, NIRO SOAVI, or Sanwa Machine Co., Inc. Other dispersionmachines can also be used in which process liquids are passed at highpressure through orifices of various shapes arranged in such a directionthat the process liquids collide with each other. Typical models of thistype include Microfluidizer (produced by Microfluidics), Starburst(Sugino Machine Ltd.), and Nanomizer (Yoshida Kikai Co., Ltd.), etc.

The pulverization pressure of the high-pressure homogenizer ispreferably about 300 to 1000 bar, more preferably about 300 to 600 bar.The inlet temperature of the high-pressure homogenizer may be suitablyselected from a wide range, but is generally about 1 to 70° C.,preferably about 5 to 40° C.

By carrying out the second pulverization step under the aboveconditions, the mean particle size of the aripiprazole in the finalsuspension is preferably adjusted to about 1 to 10 μm, preferably 1 to 5μm, more preferably 2 to 4 μm, most preferably 2 to 3 μm. Thearipiprazole suspension having a mean particle size of 2 to 3 μm isuseful because it has an excellent absorption profile and undergoes nosedimentation during manufacturing process.

The second pulverization step of step (C) may be carried out by passingthe suspension through a high-pressure homogenizer plural times. In sucha case, discrete-pass method and recirculation method may be employed,giving similar results (see Examples 1-5 and Example 6 described later).Both systems may also be combined (see Example 7, described later).

The discrete-pass method specifically refers to a method in which asuspension is processed by passing portions of the suspension through,for example, a high-pressure homogenizer until all portions thereof areprocessed while recovering the processed suspension. When the suspensionis processed plural times by discrete-pass method, the recoveredsuspension is processed by passing portions of the recovered suspensionthrough a high-pressure homogenizer until all portions thereof areprocessed while recovering the processed suspension, and this procedureis repeated.

The recirculation method specifically refers to a method in which a tankor vessel containing a suspension, connected to the inlet of, e.g., ahigh-pressure homogenizer, is also connected to the outlet of thehomogenizer via a recycle line, and the suspension in the tank or vesselis continuously processed by the homogenizer, without being recovered,so that the processed suspension is recycled through the recycle line tothe tank or vessel where it is mixed with unprocessed suspension, andthe mixture is continuously passed through the homogenizer, and thus thesuspension is processed with recirculation.

The pulverization in step (C) does not require vacuum or reducedpressure conditions, unlike in Patent Document 3.

When a high-pressure homogenizer is used in both the first and secondpulverization steps, steps (B) and (C) of the production methodcomprising the above-mentioned steps (A) to (C) of the invention arepreferably carried out as shown in the following steps (BB) and (CC),respectively.

Step (BB)

Step (BB) of the invention is a first pulverization step in which thesterile primary suspension obtained in step (A) is pulverized using ahigh-pressure homogenizer at a pulverization pressure of 50 to 200 bar,preferably 70 to 150 bar, to obtain a secondary suspension. It was foundthat this step, when adopted, solves the clogging problem mentionedabove.

In other words, the use of the high-pressure homogenizer at apulverization pressure within the range of 50 to 200 bar, preferably 70to 150 bar, prevents the clogging of the flow path of the high-pressurehomogenizer.

The inlet temperature of the high-pressure homogenizer may be suitablyselected from a wide range, but generally is about 1 to 50° C.,preferably about 5 to 40° C.

A sterile secondary suspension is obtained in this manner.

Step (CC)

Step (CC) of the invention is a second pulverization step in which thesterile secondary suspension obtained in step (BB) is pulverized using ahigh-pressure homogenizer at a pulverization pressure of 200 to 1000 barto obtain a sterile final suspension. This step provides an aripiprazolesuspension having the desired mean particle size of 1 to 10 μm,preferably 1 to 5 μm, more preferably 2 to 4 μm, most preferably about2.5 μm.

In step (CC), the pulverization pressure of the high-pressurehomogenizer needs to be increased, compared with the pulverizationpressure in step (BB). Generally, the pulverization pressure in step(CC) is preferably set higher than that of step (BB) by about 100 to 900bar, particularly about 200 to 500 bar.

Preferred pulverization pressure of the high-pressure homogenizer instep (CC) is 200 to 1000 bar, particularly about 300 to 600 bar.

Also, when the pulverization is carried out plural times in step (CC),the pulverization pressure can be increased stepwise within the range of200 to 1000 bar. In this case, the final pressure is preferably about300 to 1000 bar, more preferably about 300 to 600 bar.

The inlet temperature of the high-pressure homogenizer is suitablyselected from a wide range, but is generally about 1 to 50° C.,preferably about 5 to 40° C.

The second pulverization step of step (CC) may be carried out by passingthe suspension through a high-pressure homogenizer plural times. Thediscrete-pass method and a recirculation method mentioned above may beemployed, giving similar results. Both methods may also be combined.

The pulverization in step (CC) does not require vacuum or reducedpressure conditions, unlike in Patent Document 3.

In the invention, it is possible to perform cleaning and sterilizationof the surfaces that are exposed to liquids, of the machines used in theinvention, such as a high shear pulverizing machine, a dispersionmachine that applies shear force to a material to be processed, acolloid mill, an ultrasonic dispersion machine, and a high-pressure jettype emulsifying dispersion machine, by conducting clean-in-place (CIP)and sterilization-in-place (SIP). In-line sterilization is alsopossible. CIP may be carried out using water, hot water, alkaline water,acidic water, or organic solvent, with optional addition of one or morecleaning agents conventionally used, such as alkaline detergents,neutral detergents and acidic detergents. SIP may be carried out usingpure steam, high pressure high temperature water, etc.

Thus, a sterile aripiprazole suspension wherein the aripiprazole has amean particle size of 1 to 10 μm is obtained by aseptically pulverizing,in step (b), a sterile primary aripiprazole suspension produced in step(a) using a high shear pulverizing machine (such as, a high-shearhomomixer), a dispersion machine that applies shear force to a materialto be processed, a colloid mill, an ultrasonic dispersion machine, or ahigh-pressure jet type emulsifying dispersion machine (such as ahigh-pressure homogenizer), whose surfaces exposed to liquids have beensterilized, to form a sterile secondary suspension, and asepticallypulverizing the resulting sterile secondary suspension in step (c) usinga high-pressure jet type emulsifying dispersion machine (such as ahigh-pressure homogenizer), whose surfaces exposed to liquids have beensterilized.

Aripiprazole Aqueous Suspension

The aripiprazole in the aripiprazole aqueous suspension produced by theproduction method of the invention has a mean particle size of 1 to 10μm, preferably 1 to 5 μm, more preferably 2 to 4 μm, most preferablyabout 2 to 3 μm. According to the production method of the invention, nomatter how large the mean particle size of bulk aripiprazole is, themean particle size of aripiprazole in the suspension finally obtained iscontrolled within the above range. Therefore, the method has greatadvantages: there are few restrictions in the production of sterile bulkpowered; when using bulk powder with a large particle size, air bubbleentrainment rarely occurs during preparation of the suspension, and thedefoaming process is easy; there is no need for reduced pressure, andthe possibility of contamination from outside air is significantlydecreased.

According to the production method of the invention, a homogeneous finalsuspension free of coarse aripiprazole particles can be produced, andtherefore, the final suspension obtained (namely, the desiredaripiprazole suspension) may be filtered for removing foreignsubstances, if so desired. The filter to be used has a pore size suchthat the filter has a nominal filtration rating of 10 to 225 μm,preferably 20 to 70 μm. Therefore, the production method of theinvention may further comprise the step of filtering the finalsuspension obtained in step (c) with a filter having a nominalfiltration rating of 10 to 225 μm.

The resulting final suspension (namely, the desired aripiprazolesuspension) preferably has an aripiprazole concentration of about 10 to400 mg/ml, more preferably about 50 to 250 mg/ml, most preferably 100mg/ml.

The sterile aripiprazole suspension obtained by the production method ofthe invention is administered, for example, intramuscularly andsubcutaneously, as formulation for injection.

Method for Producing Freeze-Dried Formulation

The sterile aripiprazole suspension obtained by the aforementionedmethod may be freeze-dried to produce a freeze-dried formulation.

More specifically, the final aripiprazole suspension may be freeze-driedinto a freeze-dried formulation of a desired polymorphic form (ananhydrate, Hydrate A, or a mixture of them). To obtain a freeze-driedformulation of Aripiprazole Hydrate A, a monohydrate or Hydrate A isused as bulk aripiprazole, and the Hydrate A suspension obtained by themethod of the invention is subjected to the following freeze-dryingcycle.

The freeze-drying cycle comprises cooling the suspension to −20° C. to−55° C. at a suitable cooling rate to freeze the suspension, andperforming a drying step at a temperature below around 0° C. (preferablyaround 0° C. to −15° C.) under a suitable vacuum (e.g. about 1 to 100Pa) and for a suitable duration (e.g. until the freeze-dried formulationis obtained; typically for about 10 to 100 hours).

If a freeze-dried formulation containing aripiprazole in anhydrous formis desired, aripiprazole in the form of a monohydrate or anhydrouscrystals is used as the bulk aripiprazole, and the suspension obtainedby the method of the invention is subjected to the followingfreeze-drying cycle. The freeze-drying cycle comprises the three steps(freezing, primary drying, secondary drying). Specifically, thefreeze-drying cycle comprises cooling the suspension to −20° C. to −55°C. at a suitable cooling rate to freeze the suspension; performingprimary drying at a temperature below around 0° C. (preferably around 0°C. to −20° C.) under a suitable vacuum (e.g. about 1 to 100 Pa) and fora suitable duration (typically for about 10 to 100 hours); andperforming secondary drying at a temperature above around 0° C.(preferably 0° C. to 60° C.) under a suitable vacuum (e.g. about 0.1 to20 Pa) and for a suitable duration (e.g. until the freeze-driedformulation is obtained; typically for about 10 to 100 hours).

The freeze-dried formulation thus produced can be easily reconstitutedinto a desired aripiprazole suspension using water for injectionimmediately before the administration. Therefore, the freeze-driedformulation is useful as a formulation immediately prepared before use.Even by a reconstitution method as simple as adding water for injectionto the formulation and shaking the mixture by hand, a homogeneousaripiprazole suspension can be obtained.

EXAMPLES

Examples are provided below to describe the present invention in furtherdetail.

In each example, the mean particle size is the volume mean diametermeasured with a laser-light scattering (LLS) diffraction particle sizeanalyzer (laser diffraction particle size analyzer SALD-3000J, ShimadzuCorp.). The terms “10% diameter”, “50% diameter”, and “90% diameter”refer to, in particle size distribution, the particle diameter of thepoint where the distribution curve of integration (%) intersects with10% value of the integrated value, the particle diameter of the point atthe intersection with 50% value, and the particle diameter of the pointat the intersection with 90% value, respectively. Measurement conditionsare as follows. Medium: water; refractive index: 2.00 to 0.20i; cell:flow cell.

In each example, both steps of preparing a vehicle and combining bulkaripiprazole and the vehicle to form a primary suspension were carriedout at room temperature (20 to 30° C.), unless otherwise specified. Thefirst pulverization step for pulverizing the primary suspension wascarried out at 20 to 45° C., unless otherwise specified.

The high-pressure homogenizer used in each example is a commerciallyavailable high-pressure homogenizer (trade name “PANDA 2K Type”,manufactured by NIRO SOAVI).

Example 1

(a) Sodium carboxymethyl cellulose (18.30 g), 91.52 g of mannitol, and1.63 g of sodium dihydrogen phosphate monohydrate were dissolved inpurified water. The total weight was 2059.2 g. The solution was adjustedto pH 7.0 with a 1 mol/L sodium hydroxide aqueous solution, and filteredthrough a 0.2 μm filter.

In the resulting filtrate (1872 g), bulk aripiprazole monohydrateproduced by batch crystallization (208 g; mean particle size of the bulkpowder=258 μm; 10% diameter=99 μm; 50% diameter=280 μm; 90% diameter=609μm) was dispersed to form a primary suspension.

The dispersion procedure for preparing the primary suspension wasconducted by using a Three-One Motor (produced by HEIDON) for stirringwith 100 mm-diameter blades at about 200 to 400 rpm. (The same appliesto the following examples, unless otherwise noted.)

(b) The primary suspension was pulverized with a high shear homomixer(trade name: “Clearmix (CLM-1.5S)”, produced by M Technique Co., Ltd.)at 18000 rpm for 7.5 minutes per liter. As a result, a secondarysuspension was obtained.

(c) The obtained secondary suspension was cooled or warned so as to keepthe inlet temperature at about 10° C., about 20° C., about 40° C., andabout 60° C. The suspension was pulverized by passing 10 times through ahigh-pressure homogenizer at 600 bar by discrete-pass method.

The mean particle size of the suspensions pulverized once and pulverized10 times was measured with a particle size distribution analyzer(SALD-3000J, Shimadzu Corp.). The results are shown below.

TABLE 1 Number of Times Mean Particle Size (μm) Pulverized 10° C. 20° C.40° C. 60° C. 1 5.1 5.0 4.5 4.9 10 1.8 1.9 2.3 3.9

Table 1 reveals the following:

(i) Even when bulk aripiprazole monohydrate produced by batchcrystallization was used, passing the suspension once through ahigh-pressure homogenizer at 600 bar at an inlet temperature of 10 to60° C. in the second pulverization (step (c)) permitted the preparationof an aripiprazole suspension with a mean particle size of 1 to 10 μm.

(ii) Passing the suspension 10 times through a high-pressure homogenizerat 600 bar at an inlet temperature of 10 to 60° C. in the secondpulverization (step (c)) enabled the preparation of an aripiprazolesuspension with a mean particle size of about 2 to 4 μm.

(iii) Passing the suspension 10 times through a high-pressurehomogenizer at 600 bar at an inlet temperature of 10 to 40° C. in thesecond pulverization (step (c)) allowed the preparation of anaripiprazole suspension with a mean particle size of about 2 to 3 μm.

This shows that a suspension with the desired mean particle size (1-10μm, preferably 1-5 μm, more preferably 2 to 4 μm) is obtained even bythe use of bulk powder with a large mean particle size, which is one ofthe effects of the present invention.

The same results as above are obtained even using sterile bulkaripiprazole and a sterile vehicle. The same applies to the followingexamples.

Example 2

Sodium carboxymethyl cellulose (45.76 g), 228.80 g of mannitol, and 4.07g of sodium dihydrogen phosphate monohydrate were dissolved in purifiedwater. The total weight was 5148 g. The solution was adjusted to pH 7.0with a 1 mol/L sodium hydroxide aqueous solution, and filtered through a0.2 μm filter.

In the resulting filtrate (1872 g), bulk aripiprazole monohydrateproduced by batch crystallization (208 g; mean particle size of the bulkpowder=239 μm; 10% diameter=99 μm; 50% diameter=276 μm; 90% diameter=632μm) was dispersed to form a primary suspension.

The primary suspension was pulverized with Clearmix (CLM-1.5S) at 18000rpm for 7.5 minutes per liter. As a result, a secondary suspension wasobtained.

The obtained secondary suspension was cooled so as to keep the inlettemperature at about 20° C., and pulverized by passing 10 times througha high-pressure homogenizer at 300 bar, 600 bar, and 1000 bar bydiscrete-pass method. The mean particle size of the suspensionspulverized once and pulverized 10 times was measured with a particlesize distribution analyzer (SALD-3000J, Shimadzu Corp.). The results areshown below.

TABLE 2 Number of Times Mean Particle Size (μm) Pulverized 300 bar 600bar 1000 bar 1 5.7 4.5 4.3 10 2.6 1.9 2.5

Table 2 indicates the following:

(i) Even when bulk aripiprazole monohydrate produced by batchcrystallization was used, passing the suspension once though ahigh-pressure homogenizer at 300 to 1000 bar enabled the preparation ofan aripiprazole suspension with a mean particle size of 1 to 10 μm.

(ii) Passing the suspension 10 times though a high-pressure homogenizerat 300 to 1000 bar allowed the preparation of an aripiprazole suspensionwith a mean particle size of 2 to 3 μm.

(iii) The preparation of an aripiprazole suspension with a mean particlesize of 2 to 3 μm is also possible at 1000 bar. However, the desiredaripiprazole suspension can be efficiently obtained at 300 to 600 bar.

Example 3

Sodium carboxymethyl cellulose (45.76 g), 228.80 g of mannitol, and 4.07g of sodium dihydrogen phosphate monohydrate were dissolved in purifiedwater. The total weight was 5148 g. The solution was adjusted to pH 7.0with a 1 mol/L sodium hydroxide solution and filtered through a 0.2 μmfilter. Two kinds of sodium carboxymethyl cellulose with a viscosity of93 cps (4% aqueous solution, 25° C.) and 187 cps (4% aqueous solution,25° C.) were used.

In the resulting filtrate (1872 g), bulk aripiprazole monohydrateproduced by batch crystallization (208 g; mean particle size of the bulkpowder used for studying sodium carboxymethyl cellulose with a viscosityof 93 cps=258 μm; 10% diameter=99 μm; 50% diameter=280 μm; 90%diameter=609 μm; mean particle size of the bulk powder used for studyingsodium carboxymethyl cellulose with a viscosity of 187 cps=239 μm; 10%diameter=99 μm; 50% diameter=276 μm; 90% diameter=632 μm) was dispersedto form primary suspensions.

Each of the primary suspensions was pulverized with Clearmix (CLM-1.5S)at 18000 rpm for 7.5 minutes per liter. As a result, secondarysuspensions were obtained.

The obtained secondary suspensions were cooled so as to keep the inlettemperature at about 20° C., and pulverized by passing 10 times througha high-pressure homogenizer at 600 bar by discrete-pass method. The meanparticle size of the suspensions pulverized once and pulverized 10 timeswas measured with a particle size distribution analyzer (SAID-3000J,Shimadzu Corp.). The results are shown below.

TABLE 3 Mean Particle Size (μm) Number of Times Viscosity of SodiumCarboxymethyl Cellulose Pulverized 93 cps 187 cps 1 5.0 4.5 10 1.9 1.9

Table 3 indicates that the difference in viscosity of CMCNa does notinfluence the pulverization.

Example 4

Sodium carboxymethyl cellulose (33.28 g), 166.40 g of mannitol, and 2.96g of sodium dihydrogen phosphate monohydrate were dissolved in purifiedwater. The total weight was 3744 g. The solution was adjusted to pH 7.0with a 1 mol/L sodium hydroxide aqueous solution and filtered through a0.2 μm filter.

In the resulting filtrate (1872 g), bulk aripiprazole monohydrateproduced by batch crystallization (208 g; mean particle size of the bulkpowder=386 μm; 10% diameter=118 μm; 50% diameter=356 μm; 90%diameter=1640 μm) was dispersed to form a primary suspension. Thedispersion procedure for preparing the primary suspension was conductedby using a Three-One Motor (produced by HEIDON) for stirring with 50mm-diameter blades at about 700 to 800 rpm.

The primary suspension was pulverized with Clearmix (CLM-1.5S) at 18000rpm for 7.5 minutes per liter. As a result, a secondary suspension wasobtained.

Without temperature control, the obtained secondary suspension waspulverized by passing 10 times through a high-pressure homogenizer at600 bar by discrete-pass method. The mean particle size of thesuspensions pulverized once and pulverized 10 times was measured with aparticle size distribution analyzer (SALD-3000J, Shimadzu Corp.). Theresults are shown below.

TABLE 4 Number of Times Pulverized Mean Particle Size (μm) 1 5.0 10 3.0

Table 4 shows that even without controlling the inlet temperature, anaripiprazole suspension with a mean particle size of about 3 to 5 μm canbe prepared. When controlling the inlet temperature, an aripiprazolesuspension with a mean particle size of less than 3 microns can beobtained (see Examples 1 and 2).

Example 5

Sodium carboxymethyl cellulose (45.76 g), 228.80 g of mannitol, and 4.07g of sodium dihydrogen phosphate monohydrate were dissolved in purifiedwater. The total weight was 5148 g. Sodium carboxymethyl cellulose witha viscosity of 93 cps (4% aqueous solution, 25° C.) and 187 cps (4%aqueous solution, 25° C.) were used for preparation. The solution wasadjusted to pH 7.0 with a 1 mol/L sodium hydroxide solution and filteredthrough a 0.2 μm filter.

In the resulting filtrate (1872 g), bulk aripiprazole monohydrateproduced by batch crystallization (208 g; mean particle size of the bulkpowder=239 μm; 10% diameter=99 μm; 50% diameter=276 μm; 90% diameter=632μm) was dispersed to form primary suspensions.

The primary suspensions were pulverized with Clearmix (CLM-1.5S) at18000 rpm for 7.5 minutes per liter. As a result, secondary suspensionswere obtained.

The obtained secondary suspensions were cooled so as to keep the inlettemperature at about 20° C., and pulverized by passing 10 times througha high-pressure homogenizer at 300 bar by discrete-pass method.

The mean particle size of the suspensions pulverized once and pulverized10 times was measured with a particle size distribution analyzer(SALD-3000J, Shimadzu Corp.). The results are shown below.

TABLE 5 Mean Particle Size (μm) Number of Times Viscosity of SodiumCarboxymethyl Cellulose Pulverized 93 cps 187 cps 1 5.3 5.7 10 2.5 2.6

Table 5 reveals that in the second pulverization step, even though thepulverization pressure of the high-pressure homogenizer is 300 bar, thedifference in CMCNa viscosity does not affect the pulverization, as inExample 3.

Example 6

Sodium carboxymethyl cellulose (183 g), 915 g of mannitol, and 16.3 g ofsodium dihydrogen phosphate monohydrate were dissolved in purifiedwater. The total weight was 20592 g. The solution was adjusted to pH 7.0with a 1 mol/L sodium hydroxide aqueous solution and filtered through a0.2 μm filter.

In the resulting filtrate (18720 g), bulk aripiprazole monohydrateproduced by batch crystallization (2080 g; mean particle size of thebulk powder=246 μm; 10% diameter=103 μm; 50% diameter=260 μm; 90%diameter=548 μm) was dispersed to form a primary suspension.

The primary suspension was pulverized with Clearmix (CLM-9S) at 5700 rpmfor 2.1 minutes per liter. As a result, a secondary suspension wasobtained.

The obtained secondary suspension (500 mL) was recirculated through ahigh-pressure homogenizer, and cooled at the outlet of the high-pressurehomogenizer to adjust the inlet temperature at about 15° C. to about 25°C. The suspension was pulverized for 32.5 minutes at a pulverizationpressure of 500 bar, while being discharged from the high-pressurehomogenizer at a rate of 155 mL/min.

The mean particle size of the suspensions pulverized for 3.25 minutesand 32.5 minutes was measured with a particle size distribution analyzer(SALD-3000J, Shimadzu Corp.). The results are shown below.

TABLE 6 Pulverization Time (Minutes) Mean Particle Size (μm) 3.25 3.532.5 1.7

Table 6 shows that the desired pulverization is also possible byrecirculation method, like pulverization by discrete-pass method as usedin Examples 1 to 5. Additionally, it is seen that even when thepulverization by recirculation method is repeatedly performed over along time, the mean particle size do not fall below 1 μm.

Example 7

Sodium carboxymethyl cellulose (45.76 g), 228.80 g of mannitol, and 4.07g of sodium dihydrogen phosphate monohydrate were dissolved in purifiedwater. The total weight was 5148 g. The solution was adjusted to pH 7.0with a 1 mol/L sodium hydroxide aqueous solution and filtered through a0.2 μm filter.

In the resulting filtrate (1872 g), bulk aripiprazole monohydrateproduced by batch crystallization (208 g; mean particle size of the bulkpowder=256 μm; 10% diameter=109 μm; 50% diameter=272 μm; 90%diameter=566 μm) was dispersed to form a primary suspension.

The primary suspension was pulverized using Clearmix (CLM-1.5S) at 18000rpm for 7.5 minutes per liter. As a result, a secondary suspension wasobtained.

The obtained secondary suspension (500 mL) was cooled so as to keep theinlet temperature at about 20° C., and pulverized by passing four timesthrough a high-pressure homogenizer at 500 bar. Subsequently, thesuspension was circulated through a high-pressure homogenizer, andcooled at the outlet of the high-pressure homogenizer to adjust theinlet temperature at about 20° C. The suspension was further pulverizedby recirculation method for 42 minutes at a pulverization pressure of500 bar, while being discharged at a rate of 155 mL/min.

The mean particle size of the suspensions pulverized once, pulverizedfour times by discrete-pass method, and pulverized four times bydiscrete-pass method and further pulverized for 42 minutes byrecirculation method was measured with a particle size distributionanalyzer (SALD-3000J, Shimadzu Corp.). The results are shown below.

TABLE 7 Number of Times Pulverized, or Pulverization Time Mean ParticleSize (μm) 1 4.0 4 2.6 42 Minutes after Four- 1.6 Time Pulverization¹⁾¹⁾The suspension was pulverized four times by discrete-pass method andfurther pulverized for 42 minutes by recirculation method.

Table 7 shows that the discrete-pass method may be combined with therecirculation method. Moreover, even when the recirculationpulverization is repeatedly performed over a long time, the meanparticle size do not fall below 1 μm.

Example 8

Sodium carboxymethyl cellulose (450 g), 2250 g of mannitol, 40 g ofsodium dihydrogen phosphate monohydrate, and 160 g of a 1 mol/L sodiumhydroxide aqueous solution were dissolved in purified water. The totalweight was 50625 g. The solution was filtered through a 0.2 μm filter.In the filtrate (748.8 g), bulk aripiprazole monohydrate produced bybatch crystallization (83.2 g; mean particle size of the bulk powder=256μm; 10% diameter=109 μm; 50% diameter=272 μm; 90% diameter=566 μm) wasdispersed to form a primary suspension.

The primary suspension was pulverized with a dispersion machine thatapplies shear force to a material to be processed (trade name: “T-50Basic”, produced by IKA Japan, Inc.) using a shaft available under thegeneric name of shaft generator (trade name: “S50N-G45G”, produced byIKA Japan, Inc.) at 6400 rpm for 7.5 minutes per liter. As a result, asecondary suspension was obtained.

The obtained secondary suspension was cooled so as to keep the inlettemperature at about 20° C., and pulverized five times in total bypassing through a high-pressure homogenizer once at 300 bar and fourtimes at 500 bar by discrete-pass method. The mean particle size of thesuspensions pulverized once and pulverized five times was measured witha particle size distribution analyzer (SALD-3000J, Shimadzu Corp.). Theresults are shown below.

TABLE 8 Number of Times Pulverized Mean Particle Size (μm) 1 6.4 5 2.7

Table 8 indicates that any pulverizing machines may be used for thefirst pulverization as long as they have some degree of shear force topulverize bulk powder. Not only the aforementioned high shear homomixers(e.g., Clearmix) but also dispersion machines (e.g., “T-50 Basic”,produced by IKA Japan, Inc.) are usable.

Example 9

Sodium carboxymethyl cellulose (450 g), 2250 g of mannitol, 40 g ofsodium dihydrogen phosphate monohydrate, and 160 g of a 1 mol/L sodiumhydroxide aqueous solution were dissolved in purified water. The totalweight was 50625 g. The solution was filtered through a 0.2 μm filter.In the filtrate (748.8 g), bulk aripiprazole monohydrate produced bybatch crystallization (83.2 g; mean particle size of the bulk powder=256μm; 10% diameter=109 μm; 50% diameter=272 μm; 90% diameter=566 μm) wasdispersed to form a primary suspension.

The primary suspension was cooled so as to keep the inlet temperature atabout 20′C, and pulverized six times in total by discrete-pass method bypassing through a high-pressure homogenizer once at 100 bar (firstpulverization step), and once at 300 bar and four times at 500 bar(second pulverization step). The mean particle size of the suspensionspulverized once, pulverized twice, and pulverized six times was measuredwith a particle size distribution analyzer (SALD-3000J, Shimadzu Corp.).

The results are shown below.

TABLE 9 Number of Times Pulverized Mean Particle Size (μm) 1 18.6 2 4.76 2.4

Table 9 shows that even a high-pressure homogenizer can be used for thefirst pulverization step without inducing clogging in the line, if alower pulverization pressure is used.

Example 10

Sodium carboxymethyl cellulose (16.64 g), 83.20 g of mannitol, and 1.48g of sodium dihydrogen phosphate monohydrate were dissolved in purifiedwater. The total weight was 3704 g. The solution was adjusted to pH 7.0with a 1 mol/L sodium hydroxide aqueous solution and filtered through a0.2 μm filter.

In the resulting filtrate (1852 g), bulk aripiprazole monohydrateproduced by batch crystallization (208 g; mean particle size of the bulkpowder=238 μm; 10% diameter=72 μm; 50% diameter=274 μm; 90% diameter=811μm) was dispersed to form a primary suspension.

The primary suspension was pulverized with Clearmix (CLM-1.5S) at 18000rpm for 7.5 minutes per liter. As a result, a secondary suspension wasobtained.

Without temperature control, the obtained secondary suspension waspulverized by passing 10 times through a high-pressure homogenizer at600 bar by discrete-pass method. The mean particle size of thesuspensions pulverized once and pulverized 10 times was measured with aparticle size distribution analyzer (SALD-3000J, Shimadzu Corp.). Theresults are shown below.

TABLE 10 Number of Times Pulverized Mean Particle Size (μm) 1 4.5 10 3.4

Table 10 indicates that even without controlling the inlet temperature,an aripiprazole suspension with a mean particle size of about 3 to 5 μmcan be prepared. When controlling the inlet temperature, an aripiprazolesuspension with a mean particle size of less than 3 microns can beobtained (see Example 11 below).

Example 11

Sodium carboxymethyl cellulose (16.64 g), 83.20 g of mannitol, and 1.48g of sodium dihydrogen phosphate monohydrate were dissolved in purifiedwater. The total weight was 3704 g. The solution was adjusted to pH 7.0with a 1 mol/L sodium hydroxide aqueous solution and filtered through a0.2 μm filter.

In the resulting filtrate (1852 g), bulk aripiprazole monohydrateproduced by batch crystallization (208 g; mean particle size of the bulkpowder=238 μm; 10% diameter=72 μm; 50% diameter=274 μm; 90% diameter=811μm) was dispersed to form a primary suspension.

The primary suspension was pulverized with Clearmix (CLM-1.5S) at 18000rpm for 7.5 minutes per liter. As a result, a secondary suspension wasobtained.

The obtained secondary suspension was cooled so as to keep the inlettemperature at about 20° C., and pulverized by passing 10 times througha high-pressure homogenizer at 600 bar by discrete-pass method.

The mean particle size of the suspensions pulverized once and pulverized10 times was measured with a particle size distribution analyzer(SALD-3000J, Shimadzu Corp.). The results are shown below.

TABLE 11 Number of Times Pulverized Mean Particle Size (μm) 1 4.6 10 1.9

Table 11 indicates that even when the concentration of CMCNa as asuspending agent is low, first pass allows the preparation of asuspension with a mean particle size of 1 to 5 μm, and 10-time passingallows the preparation of a suspension with a mean particle size of 2μm.

Example 12

Sodium carboxymethyl cellulose (16.64 g), 83.20 g of mannitol, and 1.48g of sodium dihydrogen phosphate monohydrate were dissolved in purifiedwater. The total weight was 3704 g. The solution was adjusted to pH 7.0with a 1 mol/L sodium hydroxide aqueous solution and filtered through a0.2 μm filter.

In the resulting filtrate (1852 g), bulk aripiprazole monohydrateproduced by batch crystallization (208 g; mean particle size of the bulkpowder=258 μm; 10% diameter=99 μm; 50% diameter=280 μm; 90% diameter=609μm) was dispersed to form a primary suspension.

The primary suspension was pulverized with Clearmix (CLM-1.5S) at 18000rpm for 7.5 minutes per liter. As a result, a secondary suspension wasobtained.

The obtained secondary suspension was cooled or warmed so as to keep theinlet temperature at about 10° C., about 20° C., about 40° C., and about60° C., and pulverized by passing 10 times through a high-pressurehomogenizer at 600 bar by discrete-pass method. The mean particle sizeof the suspensions pulverized once and pulverized 10 times was measuredwith a particle size distribution analyzer (SALD-3000J, Shimadzu Corp.).The results are shown below.

TABLE 12 Number of Times Mean Particle Size (μm) Pulverized 10° C. 20°C. 40° C. 60° C. 1 4.6 4.4 4.5 4.7 10 1.8 2.1 2.3 4.2

Table 12 indicates the following:

(i) Even when the concentration of CMCNa is low, a suspension with amean particle size of 1 to 5 μm can be prepared as in Example 1.

(ii) Even when the concentration of CMCNa is low, a suspension with amean particle size of 2 to 3 μm can be prepared as in Example 1, byadjusting the inlet temperature to 40° C. or less.

Example 13

Sodium carboxymethyl cellulose (8.32 g), 41.60 g of mannitol, and 0.74 gof sodium dihydrogen phosphate monohydrate were dissolved in purifiedwater. The total weight was 1852 g. The solution was adjusted to pH 7.0with a 1 mol/L sodium hydroxide aqueous solution and filtered through a0.2 μm filter.

In the obtained filtrate (740.8 g), bulk aripiprazole monohydrateproduced by batch crystallization (83.2 g; mean particle size of thebulk powder=256 μm; 10% diameter=99 μm; 50% diameter=280 μm; 90%diameter=609 μm) was dispersed to form a primary suspension. Thedispersion procedure for preparing the primary suspension was conductedby using Three One Motor (produced by HEIDON) for stirring with 50mm-diameter blades at about 300 to 500 rpm.

The primary suspension was pulverized with Clearmix (CLM-1.5S) at 18000rpm for 7.5 minutes per liter. As a result, a secondary suspension wasobtained.

The obtained secondary suspension (450 mL) was circulated through ahigh-pressure homogenizer, and cooled at the outlet of the high-pressurehomogenizer to adjust the inlet temperature at about 20° C.

The suspension was pulverized by recirculation method for 72.5 minutesat a pulverization pressure of 500 bar, while being discharged from thehigh-pressure homogenizer at a rate of 155 mL/min. The mean particlesize of the suspensions pulverized for 14.5 minutes and pulverized for72.5 minutes was measured with a particle size distribution analyzer(SAID-3000J, Shimadzu Corp.). The results are shown below.

TABLE 13 Pulverization Time (Minutes) Mean Particle Size (μm) 14.5 2.272.5 1.5

Table 13 shows that even though the concentration of CMCNa is low, thedesired pulverization is possible by recirculation method; additionally,even when the recirculation pulverization is repeatedly performed over along time, the mean particle size do not fall below 1 pin.

Example 14

Each of aripiprazole suspensions obtained by the method shown inExamples 1 to 13 (2.5 mL) was poured into a glass vial, and the vial waspartially stoppered with a rubber stopper. The vials were transferred toa freeze-dryer and lyophilized under the following conditions:

(a) Freezing: The vials were cooled to −40° C. at 1′C/min., and thenkept at −40° C. for 6 hours;

(b) Drying: The chamber pressure was lowered to about 13 Pa, and theshelf temperature of the freeze-dryer was increased to −5° C. at a rateof 0.3° 12/min.; drying was then continued for 55.5 hours while thedegree of vacuum was kept at about 13 Pa, and the shelf temperature keptat about −5° C.;

(c) The vials were stoppered under atmospheric pressure or partialvacuum using nitrogen or air, and then removed from the freeze-dryer;and

(d) The vials were sealed with aluminum seals.

The aripiprazole each of the resulting freeze-dried aripiprazolesuspensions was Hydrate A.

Example 15

Each of the aripiprazole suspensions obtained by the method shown inExamples 1 to 13 was poured into a glass vial, and the vial waspartially stoppered with a rubber stopper. The vials were transferred toa freeze-dryer and lyophilized under the following conditions:

(a) Freezing: The vials were cooled to −40° C. at 1° 2/min., and thenkept at −40° C. for 6 hours;

(b) Primary drying: The chamber pressure was lowered to about 13 Pa, andthe shelf temperature of the freeze-dryer was increased to −5° C. at arate of 0.3° C./min.; primary drying was then continued for 55.5 hourswhile the degree of vacuum was kept at about 13 Pa, and the shelftemperature kept at about −5° C.;

(c) Secondary drying: The shelf temperature was increased to 25° C., anddrying continued for 24 hours while the degree of vacuum was kept atabout 13 Pa; the shelf temperature was then increased to 50° C., anddrying continued for 24 hours while the degree of vacuum was kept atabout 13 Pa;

(d) The vials were stoppered under atmospheric pressure or partialvacuum using nitrogen or air, and then removed from the freeze-dryer;and

(e) The vials were sealed with aluminum seals.

The aripiprazole each of the resulting freeze-dried aripiprazolesuspensions was in the anhydrous form.

1. A method for producing an aripiprazole suspension comprising thesteps of: (a) combining bulk aripiprazole and a vehicle to form aprimary suspension; (b) subjecting the primary suspension to firstpulverization to form a secondary suspension; and (c) subjecting thesecondary suspension to second pulverization to form a final suspension.2. The method according to claim 1, wherein in the first pulverizationof step (b), the secondary suspension is formed by pulverizing theprimary suspension using a high shear pulverizing machine, a dispersionmachine that applies shear force to a material to be processed, acolloid mill, an ultrasonic dispersion machine, or a high-pressure jettype emulsifying dispersion machine, and in the second pulverization ofstep (c), the final suspension is formed by pulverizing the secondarysuspension using a high-pressure jet type emulsifying dispersionmachine.
 3. The method according to claim 1, wherein in the firstpulverization of step (b), the secondary suspension is formed bypulverizing the primary suspension using a high shear pulverizingmachine or a dispersion machine that applies shear force to a materialto be processed, and in the second pulverization of step (c), the finalsuspension is formed by pulverizing the secondary suspension using ahigh-pressure homogenizer.
 4. The method according to claim 3, whereinin step (c), the high-pressure homogenizer is used at a pulverizationpressure of 300 to 1000 bar.
 5. The method according to claim 3, whereinin step (c), the high-pressure homogenizer is used at a pulverizationpressure of 300 to 600 bar.
 6. The method according to claim 3, whereinin step (c), the high-pressure homogenizer is used at an inlettemperature of 1 to 70° C.
 7. The method according to claim 1, whereinin the first pulverization of step (b), the secondary suspension isformed by pulverizing the primary suspension using a high-pressurehomogenizer, and in the second pulverization of step (c), the finalsuspension is formed by pulverizing the secondary suspension using ahigh-pressure homogenizer.
 8. The method according to claim 7, whereinin the first pulverization of step (b), the secondary suspension isformed by pulverizing the primary suspension using a high-pressurehomogenizer at a pulverization pressure of 50 to 200 bar, and in thesecond pulverization of step (c), the final suspension is formed bypulverizing the secondary suspension using a high-pressure homogenizerat a pulverization pressure of 200 to 1000 bar, wherein the differencebetween the pulverization pressure in step (b) and the pulverizationpressure in step (c) is 100 to 900 bar.
 9. The method according to Item8, wherein in step (b), the pulverization pressure of the high-pressurehomogenizer is in the range of 50 to 200 bar, and in step (c), thepulverization is carried out plural times and the pulverization pressureis raised stepwise within the range of 200 to 1000 bar.
 10. The methodaccording to claim 9, wherein in step (c), the final pulverizationpressure of the high-pressure homogenizer is 300 to 600 bar.
 11. Themethod according to claim 7, wherein in steps (b) and (c), thehigh-pressure homogenizer is used at an inlet temperature of 1 to 50° C.12. The method according to claim 1, wherein the vehicle contains atleast one suspending agent selected from the group consisting ofcarboxymethyl cellulose, carboxymethyl celllose salts, hydroxypropylcellulose, hydroxypropylethyl cellulose, hydroxypropylmethyl celluloseand polyvinyl pyrrolidone.
 13. The method according to claim 1, whereinthe bulk aripiprazole contains aripiprazole particles with a particlesize of 100 μm or more in an amount of 10% or more, and has a meanparticle size of 20 μm to 1000 μm.
 14. The method according to claim 1,wherein the bulk aripiprazole has a mean particle size of more than 100μm.
 15. The method according to claim 1, wherein the bulk aripiprazolehas a mean particle size of 110 μm to 1000 μm.
 16. The method accordingto claim 1, wherein the bulk aripiprazole has a mean particle size of200 μm to 400 μm.
 17. The method according to claim 1, wherein thearipiprazole in the aripiprazole suspension has a mean particle size of1 to 10 μm.
 18. The method according to claim 1, wherein thearipiprazole in the aripiprazole suspension has a mean particle size of1 to 5 μm.
 19. The method according to claim 1, wherein the aripiprazolein the aripiprazole suspension has a mean particle size of 2 to 4 μm.20. The method according to claim 1, wherein the aripiprazole in thearipiprazole suspension has a mean particle size of 2 to 3 μm.
 21. Themethod according to claim 1, comprising the steps of: (I) combiningsterile bulk aripiprazole with a mean particle size of 200 μm to 400 μmand a sterile vehicle to form a sterile primary suspension; (II)subjecting the sterile primary suspension to first pulverization using ahigh shear pulverizing machine or a dispersion machine that appliesshear force to a material to be processed, to form a sterile secondarysuspension; and (III) subjecting the sterile secondary suspension tosecond pulverization using a high-pressure homogenizer to form a sterilefinal suspension; wherein the aripiprazole in the sterile finalsuspension has a mean particle size of 1 to 10 μm.
 22. The methodaccording to claim 1, wherein the bulk aripiprazole is in the formselected from the group consisting of monohydrate and Anhydride CrystalsB.
 23. The method according to claim 1, further comprising the step offiltering the final suspension with a filter having a nominal filtrationrating of 10 to 225 μm.
 24. A method for producing a freeze-driedformulation of Aripiprazole Hydrate A, the method comprising the stepsof: cooling the suspension produced by the method according to claim 1and containing Aripiprazole Hydrate A, to −20 to −55° C. to freeze thesuspension; and subsequently performing drying at below about 0° C. 25.A method for producing a freeze-dried formulation containingaripiprazole in anhydrous form, the method comprising the steps of: (1)cooling the aripiprazole suspension produced by the method according toclaim 1 using bulk aripiprazole in the form of a monohydrate oranhydrous crystals to −20 to −55° C. to freeze the suspension; (2)performing primary drying at below about 0° C.; and (3) performingsecondary drying at above about 0° C.